Protective Efficacy of Neutralizing Monoclonal Antibodies in a Nonhuman Primate Model of Ebola Hemorrhagic Fever

Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF

A novel model of lethal Hendra virus infection in African green monkeys and the effectiveness of ribavirin treatment

The henipaviruses, Hendra virus (HeV) and Nipah virus (NiV), are emerging zoonotic paramyxoviruses that can cause severe and often lethal neurologic and/or respiratory disease in a wide variety of mammalian hosts, including humans. There are presently no licensed vaccines or treatment options approved for human or veterinarian use. Guinea pigs, hamsters, cats, and ferrets, have been evaluated as animal models of human HeV infection, but studies in nonhuman primates (NHP) have not been reported, and the development and approval of any vaccine or antiviral for human use will likely require efficacy studies in an NHP model. Here, we examined the pathogenesis of HeV in the African green monkey (AGM) following intratracheal inoculation. Exposure of AGMs to HeV produced a uniformly lethal infection, and the observed clinical signs and pathology were highly consistent with HeV-mediated disease seen in humans. Ribavirin has been used to treat patients infected with either HeV or NiV; however, its utility in improving outcome remains, at best, uncertain. We examined the antiviral effect of ribavirin in a cohort of nine AGMs before or after exposure to HeV. Ribavirin treatment delayed disease onset by 1 to 2 days, with no significant benefit for disease progression and outcome. Together our findings introduce a new disease model of acute HeV infection suitable for testing antiviral strategies and also demonstrate that, while ribavirin may have some antiviral activity against the henipaviruses, its use as an effective standalone therapy for HeV infection is questionable. Copyrigh

Comparative Pathogenesis of Three Human and Zoonotic SARS-CoV Strains in Cynomolgus Macaques

The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. While there were significant differences in the number of host genes differentially regulated during the host responses between the three SARS-CoV strains, the top pathways and functions were similar and only apparent early during infection with the majority of genes associated with interferon signaling pathways. This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use

Pathogenesis and Host Response in Syrian Hamsters following Intranasal Infection with Andes Virus

Hantavirus pulmonary syndrome (HPS), also referred to as hantavirus cardiopulmonary syndrome (HCPS), is a rare but frequently fatal disease caused by New World hantaviruses. In humans HPS is associated with severe pulmonary edema and cardiogenic shock; however, the pathogenesis of this disease remains unclear largely due to a lack of suitable animal models for the study of disease progression. In this study we monitored clinical, virological, pathophysiological parameters and host immunological responses to decipher pathological factors and events in the lethal Syrian hamster model of HPS following intranasal inoculation of Andes virus. Transcriptional profiling of the host gene responses demonstrated a suppression of innate immune responses in most organs analyzed during the early stage of infection, except for in the lung which had low level activation of several pro-inflammatory genes. During this phase Andes virus established a systemic infection in hamsters, with viral antigen readily detectable in the endothelium of the majority of tissues analyzed by 7–8 days post-inoculation. Despite wide-spread infection, histological analysis confirmed pathological abnormalities were almost exclusively found in the lungs. Immediately preceding clinical signs of disease, intense activation of pro-inflammatory and Th1/Th2 responses were observed in the lungs as well as the heart, but not in peripheral organs, suggesting that localized immune-modulations by infection is paramount to pathogenesis. Throughout the course of infection a strong suppression of regulatory T-cell responses was noted and is hypothesized to be the basis of the aberrant immune activations. The unique and comprehensive monitoring of host immune responses to hantavirus infection increases our understanding of the immuno-pathogenesis of HPS and will facilitate the development of treatment strategies targeting deleterious host immunological responses

A Hendra virus G glycoprotein subunit vaccine protects African green monkeys from Nipah virus challenge

In the 1990s, Hendra virus and Nipah virus (NiV), two closely related and previously unrecognized paramyxoviruses that cause severe dis

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility

Community Hospital Response to COVID-19 Outbreak

Since early 2020, the world has been living through coronavirus disease 2019 (COVID-19). Westchester County, New York, was one of the hardest and earliest hit places in the United States. Working within a community emergency department amid the rise of a highly infectious disease such as COVID-19 presented many challenges, including appropriate isolation, adequate testing, personnel shortages, supply shortfalls, facility changes, and resource allocation. Here we discuss our process in navigating these complexities, including the practice changes implemented within our institution to counter these unprecedented issues. These adjustments included establishing three outdoor tents to serve as triage areas; creating overflow intensive care units through conversion of areas that had previously served as the ambulatory surgery unit, post-anesthesia care unit, and endoscopy suite; increasing critical care staff to meet unprecedented need; anticipating and adapting to medical supply shortages; and adjusting resident physician roles to meet workflow requirements. By analyzing and improving upon the processes delineated below, our healthcare system should be better prepared for future pandemics

Modeling of output parameters of the silicon solar cells with i-type conductivity base crystals

Проведено експериментальне дослідження та моделювання із використанням програми PC1D ви- хідних параметрів лабораторних зразків фотоелектричних перетворювачів на основі монокристалічного кремнію і-типу електропровідності. Встановлено, що використання базових кристалів і-типу еле- ктропровідності в умовах опромінення АМ0 дозволяє отримувати рекордно високі значення густини фотоструму, котрі сягають 48,6 мА/см2. Проте їх коефіцієнт корисної дії не перевищує 11,6 %. Для розробки фізично обґрунтованого підходу до оптимізації конструктивно-технологічних рішень проана- лізовано електронну модель кремнієвого фотоелектричного перетворювача з p+-i-n+ структурою. В ході апробації моделі було одержано серію діаграм розподілу значень коефіцієнта корисної дії досліджуваних фотоелектричних перетворювачів з p+-i-n+ структурою залежно від значень послідовного і шунтувального опорів при густині діодного струму насичення 10 – 7 А/см2, 10 – 8 А/см2 та 10 – 9 А/см2. Наявність таких діаграм при проведенні розробки високоефективних фотоперетворювачів зазначеного типу дозволить не тільки суттєво зменшити витрати на пошукові дослідження, але й забезпечить досягнення необхідного у кожному конкретному випадку оптимального співвідношення між витратами на покращення діодної структури та підвищеним рівнем коефіцієнта корисної дії таких приладів.Проведено экспериментальное исследование и моделирование с использованием программы PC1D выходных параметров лабораторных образцов фотоэлектрических преобразователей на основе монокристаллического кремния і-типа электропроводности. Установлено, что использование базовых кристаллов і-типа электропроводности в условиях облучения АМ0 позволяет получить рекордно высокие значения плотности фототока, достигающие 48,6 мА/см2. Однако их коэффициент полезного действия не превышает 11,6 %. Для разработки физически обоснованного подхода к оптимизации конструктивно-технологических решений проанализирована электронная модель кремниевого фотоэлектрического преобразователя з p+-i-n+ структурою. В ходе апробации модели была получена серия диаграмм распределения значений коэффициента полезного действия исследуемых фотоэлектрических преобразователей с p+-i-n+ структурой в зависимости от значений последовательного и шунтирующего сопротивлений при плотности диодного тока насыщения 10– 7 А/см2, 10– 8 А/см2 и 10– 9 А/см2. Наличие таких диаграмм при проведении разработки высокоэффективных фотопреобразователей указанного типа позволит не только существенно уменьшить затраты на поисковые исследования, но и обеспечит достижение необходимого в каждом конкретном случае оптимального соотношения между затратами на улучшение диодной структуры та повышенным уровнем коэффициента полезного действия таких приборов.It was carried out the experimental investigation and modeling of the solar cells based on single crystal silicon with i-type conductivity laboratory samples output parameters using PC1D program. It has been found that use of i-type conductivity base crystals under AM0 irradiation allows to reach the record high photocurrent density values up to 48.6 mA/cm2. However, their efficiency does not exceed 11.6 %. To develop the physically based approach to optimize construction-technological solutions it has been analyzed the electronic model of silicon solar cells with p+-i-n+ structure. During the testing of the model we have obtained a series of diagrams with distribution of the investigated solar cells with p+-i-n+ structure efficiency values, depending on the values of series and shunt resistances at the diode saturation current density of 10 – 7 A/cm2 and 10 – 8 A/cm2 10 – 9 A/cm2. Availability of these diagrams during the development of such type highly effective solar cells will not only significantly reduce the cost of exploratory research but also will produce the required in each particular case an optimum ratio between the costs of diode structure improving and increased level of such devices efficiency